Fluid-containing pouches with reduced gas exchange and methods for making same

ABSTRACT

The invention is directed to fluid-containing pouches and to methods for forming fluid-containing pouches. In one embodiment, the invention is to a fluid-containing pouch, comprising first and second opposing sheets, and a fluid (e.g., a calibrant fluid, a reactant fluid or a wash fluid) disposed between the first and second opposing sheets. The first sheet and the second sheet have a substantially liquid and gas impermeable perimeter seal. The sheets may be sealed, for example, by one or more of heat crimping, pressure crimping, heat and pressure crimping, ultrasonic welding, metal-to-metal welding or laser welding. Fluid-containing pouches sealed according to the disclosed methods and apparatuses show substantially improvement in terms of reduced gas exchange, notably CO 2  pressurization levels.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to medical diagnostic sensor packaging. Moreparticularly, the invention relates to a system and method for sealing aone-time use medical diagnostic sensor package.

2. Background Art

In the area of blood testing on patients using various sensingtechnologies, it is well known that the sensors must be properlycalibrated if the measurement is to be performed with the desired degreeof accuracy. Recent developments in clinical diagnostics have led to thedevelopment of unitized testing systems where a sensor is packaged intoa device that is used for a single panel of tests and then discarded.These devices are typically used in conjunction with a reader that isable to interact with the device. Interactions include extracting asignal from each sensor, and optionally controlling the motion of fluidswithin the device, e.g., positioning of the sample and a calibrant fluidwith respect to the sensor. A detailed description of one such system,referred to herein as the i-STAT™ system, is found in U.S. Pat. No.5,096,669 (the '669 patent), which is jointly owned and incorporatedherein by reference.

A key feature of these sensing systems is that the devices aremanufactured and shipped to customers on a regular basis. The timebetween the manufacture and use of the device, however, can be severalmonths. As a result, devices are manufactured with labeling thatindicates the available shelf-life under a given set of conditions,e.g., six months with refrigeration, and two weeks at room temperature,among other combinations of storage conditions.

There are several reasons why shelf life of a given sensor may belimited, including, but not limited to sensor stability and calibrantfluid stability. With respect to the calibrant fluid, it is importantthat the concentration of the calibrant analyte (e.g., potassium ionconcentration, partial pressure of carbon dioxide, among others), doesnot change during storage. One solution to this problem is to storecalibrant fluids in a sealed glass vessel, or ampoule. In a sealedvessel, the walls of the vessel do not permit gas or liquid exchange.However, when devices are designed for convenient use, e.g., in thebedside or point of care testing environment, it may not be practical touse a glass storage vessel. The impracticalities can relate tofragility, and issues of packaging a glass element into a test housing,e.g., a single-use test cartridge. As a result, foil pouches withplastic layers have been used to affect the seal. For example, the '669patent discloses calibrant packs that are made with plastic-lined foilhaving a perimeter seal. Specifically, two portions of plastic-linedfoil with plastic faces abutted are sealed together to form an enclosurecontaining a liquid phase and a gas phase. Here, the perimeter seal isformed by applying sufficient heat to melt the plastic and sufficientpressure to form a contiguous plastic perimeter seal. Within theenclosure (or pouch), the liquid phase comprises a calibrant fluid,e.g., a buffered aqueous mixture containing known concentrations of theanalytes to be tested, including, for example, potassium, sodium,glucose, and lactate, among others. The gas phase in the pouch can be,for example, air or a desired gas composition, e.g., 5% carbon dioxide,20% oxygen and 75% nitrogen. The gas phase, or the dissolved gases inthe liquid phase, can also act as a calibrant, e.g., for blood gassensing of the partial pressures of oxygen and carbon dioxide, pO₂ andpCO₂ respectively.

With regard to the construction of the pouch, the choice of foil, e.g.,˜40 μm aluminum roll, is determined by its barrier properties, i.e., theresistance to transport gases, vapors and liquids. Foils are alsopreferably selected to minimize pin-holes. Various optical inspectionmeans are well known in the art for identifying pin-hole failures. Theplastic layer serves as a means for providing a seal and also protectingthe fluid from direct contact with the metal foil, which can causedegradation of one or more of the calibrant fluid components.

While the foil is generally an effective barrier, various gases, e.g.,oxygen, carbon dioxide and water vapor are soluble in plastics todifferent degrees and also can permeate the plastic matrix at a givenrate. This rate will be a function of temperature and pressure, thechemical composition of the plastic, the solvent from which it is cast,and the density of the cast material.

Where a specific gas is used for calibration purposes, e.g., a knownpartial pressure of carbon dioxide (pCO₂) to calibrate a pCO₂ sensor, itis preferable for the seal to have a low permeability and solubility forpCO₂. The dimension of the housing into which the fluid-containing pouchis to be packaged, however, may place restrictions on the sealdimensions.

Packaging of a pouch into a small plastic housing is shown in the '669patent. Here the pouch sits in a plastic base with a barb structurecapable of piercing the pouch. The pouch is held in place bydouble-sided adhesive tape attached to a plastic cover. The plasticcover has a flexible paddle directly above and aligned with the pouch.When a force is applied to the paddle, it presses the pouch against thebarb, rupturing the pouch and releasing the calibrant fluid to flowthrough a conduit and into contact with an arrays of sensors.

A further consideration, where possible, is to minimize gas exchangeacross the seal by minimizing the driving force, i.e., the difference inpressure and concentration of the analyte on either side of the seal. Areduced temperature can also reduce gas exchange, however this approachmust be used judiciously, as freezing an aqueous fluid within a pouchmay lead to undesirable effects such as seal rupture. As a consequence,refrigeration is a useful compromise.

Regarding other art, U.S. Pat. No. 6,178,832 (hereinafter the '832patent) describes a self-contained reagent chamber with fluids includingtonometered calibrants where the chamber wall includes multiple layersof materials and where at least one layer is a thin, flexible glassmaterial. The walls are extended to form a filler neck sealed by heatand pressure along a sealing line below a filler line, so that nobubbles are trapped in the reagent chamber.

U.S. Published Patent Application No. 20060013744 discloses a flexiblecontainer for a reference gas, for use in performing calibration orquality control of an apparatus for determining a gas parameter in aphysiological liquid, such as blood. The flexible container is adaptedto hold the reference gas at or close to ambient pressure.

U.S. Published Patent Application No. 20060183216 discloses a containerfor a liquid reagent, wherein the container has an outer wall and aninternal piercing member. Such a container is configured to store theliquid for periods between 6 to 18 months with minimal loss of theliquid inside, other than if the container is ruptured. The container ispreferably adapted for use with a micro-fluidic device.

U.S. Published Patent Application No. 20040222091 discloses a diagnosticdevice incorporating electrode modules and fluidics for performingchemical analyses. The device consists of a plastic card-like body withfluidic conduits and a sealed fluid reservoir contained in a foil-linedcavity. The reservoir holds a calibrant fluid that is used to calibratethe electrodes.

Conventional fluid-containing pouches of the type described in the '669patent have proved commercially successful for calibrating blood testingsensors where the pouches have an extended shelf-life withrefrigeration. However, the need exists for improved fluid-containingpouches that have an extended shelf-life without refrigeration, suchthat their contents remain substantially unaltered with extended roomtemperature storage.

SUMMARY OF THE INVENTION

It is therefore a general aspect of the invention to provide afluid-containing pouch that will obviate or minimize problems of thetype previously described. In various embodiments, the invention is tofluid-containing pouches having seals with low permeability andsolubility for gases, e.g., CO₂ gas. The reduced permeability andsolubility may be achieved, for example, by employing improved pouchseals that are formed from seal materials having low permeability andsolubility for gases, e.g., CO₂ gas. In some embodiments, the sealdimensions provide a long and tortuous path length with minimalcross-section, i.e., where the ratio of cross-sectional area to pathlength height is small. The invention is also directed to variousprocesses for forming such fluid-containing pouches.

In one embodiment, the invention is directed to a fluid-containingpouch, comprising first and second opposing sheets, and a fluid disposedbetween the first and second opposing sheets, wherein the first sheetand the second sheet have a substantially liquid and gas impermeableperimeter seal, at least a portion of which has a seal width less thanabout 4 mm, and wherein the pouch yields a Pouch Integrity Test ΔpCO₂value, as defined herein, of less than about 10 mm Hg. In addition tohaving a substantially liquid and gas impermeable seal, thefluid-containing pouch preferably has a burst strength standarddeviation of less than 12%. Such pouches are particularly well-suitedfor use in a single-use cartridge containing at least one sensor,wherein the cartridge is used in conjunction with a reader to measure ananalyte is a sample, e.g., a blood sample.

The first sheet and the second sheet optionally are folded in anundulating pattern having a plurality of bends. In a preferred aspect,the first sheet includes a first foil layer and a first plastic layer,and the second sheet includes a second foil layer and a second plasticlayer. Optionally, the pouch further comprises an interior plastic sealbead disposed at an interior edge of the perimeter seal.

In one aspect, the first sheet includes a first foil layer and a firstplastic layer, and the second sheet includes a second foil layer and asecond plastic layer, and the perimeter seal comprises a third plasticlayer disposed between the first and second foils and having an averagethickness less than the combined thickness of the first and secondplastic layers. The third plastic layer, for example, optionally has anaverage thickness that is at least about 25% less than, e.g., at leastabout 50% less than, the combined thickness of the first and secondplastic layers. In preferred embodiments, the first and second plasticlayers comprise plastic selected from the group consisting of Primacor,polyvinyl chloride, polytethylene and lacquer based on nitrocellulose,urea and acrylic resins. In one embodiment, the first sheet includes afirst foil layer and a first lacquer layer, the second sheet includes asecond foil layer and a second lacquer layer, and the first and secondfoil layers are fused to one another at the perimeter seal.

The perimeter seal preferably is formed by applying pressure in therange of from about 34.5 MN/m² to about 62.1 MN/m² and/or by applyingheat in the range of from about 200° C. to about 500° C. The perimeterseal optionally has a perimeter width of from about 1 mm to about 2 cmand optionally has a perimeter length of from about 1 cm to about 20 cm.

The fluid contained in the pouch may vary, but preferably is a calibrantfluid containing a known concentration of one or more analytes, is areactant fluid or is a wash fluid. The pouch preferably has a pouchvolume of from about 5 μL to about 5 mL. The liquid volume in the pouchpreferably is from about 50% to about 95%, based on the total pouchvolume, and the gas volume preferably is from about 5% to about 50%,based on the total pouch volume. The gas in the gas phase preferablycomprises a calibrant gas having a known concentration or partialpressure of one or more gases. The gas in the gas phase optionally isambient air.

In a preferred embodiment, the perimeter seal includes one or morecrimped regions. The one or more crimped regions preferably comprisemultiple concentric crimping rings.

In another embodiment, the invention is to a fluid-containing pouch,comprising first and second opposing sheets, and a fluid disposedbetween the first and second opposing sheets, wherein the pouch has aburst strength with a standard deviation of less than 12%.

In another embodiment, the invention is directed to a method for forminga fluid-containing pouch, comprising the steps of: (a) depositing afluid on a first sheet; (b) positioning a second sheet opposite thefirst sheet; and (c) sealing the opposing first and second sheets to oneanother and forming a sealed region having the fluid containedtherebetween, wherein the sealed region is substantially liquid and gasimpermeable. Preferably, the pouch yields a Pouch Integrity Test ΔpCO₂value, as defined herein, of less than 10 mm Hg. The process preferablyfurther comprises forming a cavity in the first sheet, and depositingthe fluid in the cavity

The sealing preferably comprises applying heat and/or pressure to thefirst sheet and second sheets. In another aspect, the sealing comprisesultra-sonic welding or laser welding. Optionally, the first sheet andthe second sheet are folded in a undulating pattern having a pluralityof bends. In a particularly preferred aspect, the first sheet includes afirst foil layer and a first plastic layer, and the second sheetincludes a second foil layer and a second plastic layer, and the step ofsealing comprises melting the first plastic layer on the first sheetwith the second plastic layer on the second sheet such that an interiorplastic seal bead is formed. The interior plastic seal beadsubstantially prevents the calibrant liquid from contacting either of orboth of the first and second foil layers.

In another embodiment, the invention is to a substantially gas-tightseal formed with plastic-lined foil, comprising two portions ofplastic-lined foil with the plastic faces abutted where adjacentportions are sealed together to isolate a first phase from a secondphase. The seal is formed by applying sufficient heat and pressure tomelt the plastic and form a plastic seal, whereby the heat and pressureare applied by a crimping element yielding one or more regions of theseal where the average thickness of plastic in the crimped region isless than the initial combined thickness of the two plastic linings, andwhereby gas transport between said first phase and said second phasethrough said plastic seal is substantially less than a seal whereplastic is not crimped during sealing. Preferably, the method isperformed with the foil on a reel. The pressure optionally is appliedwith a jig that crimps the foil. The heat and pressure optionally areapplied with ultrasonic welding.

In another embodiment, the invention is to a substantially gas-tightplastic-lined foil pouch with a perimeter seal, comprising two portionsof plastic-lined foil with the plastic faces abutted and sealed togetherto form an enclosure containing a liquid phase and a gas phase. Theperimeter seal is formed by applying sufficient heat and pressure tomelt the plastic and form a plastic perimeter layer, where the pressureis applied by a crimping element yielding one or more regions of theperimeter seal where the average thickness of plastic in the perimeterseal in the crimped regions is substantially less than the initialcombined thickness of the two plastic linings.

In another embodiment, the invention is to a method of forming asubstantially gas tight seal in a plastic-lined foil pouch, comprising:(a) forming a pocket in a first plastic-lined foil, and applying aportion of liquid into the pocket; (b) covering the pocket with a secondplastic-lined foil with the plastic faces abutted; (c) sealing the firstand second plastic-lined foils together to form a perimeter seal, wheresaid perimeter seal is formed by applying sufficient heat and pressureto melt the plastic and form a plastic perimeter layer. In thisembodiment, the pressure is applied by a crimping element yielding oneor more regions of the perimeter seal where the average thickness ofplastic in the crimped regions is substantially less than the combinedthickness of the two plastic linings, said seal forming a substantiallygas tight pouch containing a liquid phase and a gas phase.

In another embodiment, the invention is a method of forming asubstantially gas-tight plastic-lined foil pouch with a perimeter seal,comprising: (a) a first step where two portions of plastic-lined foilwith the plastic faces abutted are sealed together to form an enclosurewith a perimeter seal containing a liquid phase and a gas phase. Theperimeter seal is formed by applying sufficient heat to melt the plasticand sufficient pressure to form a contiguous plastic perimeter seal. Themethod includes (b) a second step where said perimeter seal is crimpedto yield one or more regions of the perimeter seal where the averagethickness of plastic in the crimped regions is substantially less thanthe combined thickness of the two plastic linings.

In another embodiment, the invention is to a substantially gas-tightseal formed with plastic-lined foil, comprising: two portions ofplastic-lined foil with the plastic faces abutted where adjacentportions are sealed together to isolate a first phase from a secondphase, where the seal is formed by applying sufficient ultrasonicwelding to melt the plastic and form a plastic seal. The ultrasonicwelding yields one or more regions of the plastic seal where the averagethickness of plastic in the seal region is substantially less than theinitial combined thickness of the two plastic linings, and whereby gastransport between said first phase and said second phase through saidplastic seal is substantially less than a seal where the thickness ofplastic is substantially that of the combined thickness of two plasticlinings.

In another embodiment, the invention is to a substantially gas-tightplastic-lined foil pouch with a perimeter seal, comprising two portionsof plastic-lined foil with the plastic faces abutted and sealed togetherto form an enclosure containing a liquid phase and a gas phase, wheresaid perimeter seal is formed by applying an ultrasonic weld to melt theplastic and form a contiguous plastic perimeter layer, and force aportion of plastic from the seal region into at least a portion of theperimeter of the enclosure, whereby the average thickness of plastic inthe perimeter seal is less than the initial combined thickness of thetwo plastic linings.

In another embodiment, the invention is to a method of forming asubstantially gas tight seal in a plastic-lined foil pouch comprising:(a) forming a pocket in a first plastic-lined foil; (b) applying aportion of liquid into the pocket; (c) covering the pocket with a secondplastic-lined foil with the plastic faces abutted, (d) sealing the firstand second plastic-lined foils together to form a perimeter seal, wheresaid perimeter seal is formed by applying an ultrasonic weld to melt theplastic and force a portion of plastic from the seal region into thepocket. The seal forms a substantially gas tight pocket containing aliquid phase and a gas phase, whereby the average thickness of plasticin the perimeter seal is substantially less than the combined thicknessof the two plastic linings.

In another embodiment, the invention is to a substantially gas-tightseal formed with plastic-lined foil, comprising two portions ofplastic-lined foil with the plastic faces abutted where adjacentportions are sealed together to isolate a first phase from a secondphase. The seal is formed by applying sufficient welding energy tosubstantially remove plastic from the seal region and melt the foil andform a metal-to-metal seal in said seal region. The welding energypreferably is provided by ultrasonic energy or laser energy.

In another embodiment, the invention is to a substantially gas-tightfoil pouch with an inner plastic perimeter seal and an outermetal-to-metal seal, comprising: two portions of foil with a plasticlining on predetermined regions of the foil where the regions andplastic faces are aligned, abutted and sealed together to form anenclosure, bounded by an inner plastic perimeter seal, containing aliquid phase and a gas phase, and where a surrounding portion of the twoportions of the foil are laser welded together forming an outermetal-to-metal seal.

In another embodiment, the invention is to a substantially gas-tightpouch, comprising an inner sealed plastic enclosure containing a liquidphase and a gas phase, and an outer sealed foil enclosure where twoportions of foil are laser welded together to form an outermetal-to-metal seal enclosing said plastic enclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features and advantages of the present invention will bebetter understood by reference to the detailed description of thepreferred embodiments that follows when read in conjunction with theaccompanying drawings.

FIG. 1 illustrates a schematic design for an automated form, fill, andseal process to fill and seal fluid-containing pouches.

FIG. 2 illustrates a cross sectional view of two pieces of sealing foilas they enter the automated fluid-containing pouch sealing system shownin FIG. 1.

FIG. 3 illustrates a conventional fluid-containing pouch sealing jig.

FIG. 4 illustrates a top view of a conventionally sealedfluid-containing pouch, showing areas of sealing.

FIG. 5 illustrates a micrograph of a cross-section of a seal region of afluid-containing pouch after sealing as described in U.S. Pat. No.5,096,669.

FIGS. 6A-6B illustrate cross-section micrographs of seal regions for twofluid-containing pouches following sealing according to exemplaryembodiments of the present invention.

FIGS. 7A-7C and 7E illustrate a top view, a first perspective view, aside view, and a second perspective view, respectively, of afluid-containing pouch manufactured using the system as shown in FIG. 1according to an exemplary embodiment of the present invention, and FIG.7A illustrates several variable dimensions in a manufacturing process ofthe fluid-containing pouches according to an exemplary embodiment of thepresent invention. FIG. 7D illustrates a conventionally sealedfluid-containing pouch.

FIG. 8 illustrates a cross-sectional view of a sealing jig according toan exemplary embodiment of the present invention.

FIG. 9 illustrates a close-up cross sectional view of a crimping regionof the crimping jig as shown in FIG. 8.

FIG. 10 illustrates a further close-up cross section view of crimpingregion 36 with lower sealing foil 2 placed against the lower crimpingjig.

FIGS. 11A and 11B illustrate a gas control storage vessel used to storefluid-containing pouches in a controlled gas environment for an extendedperiod of time at a controlled temperature.

FIG. 12 illustrates a disassembled view of the gas control storagevessel as shown in FIGS. 11A and 11B.

FIG. 13 illustrates an ultrasonic welding system according to anembodiment of the present invention.

FIG. 14 is a micrograph of a cross-section of a seal region of afluid-containing pouch manufactured according to an ultrasonic weldingembodiment of the present invention with Primacor located between upperand lower sealing foil layers of the fluid-containing pouch.

FIG. 15A is a micrograph of a cross-section of another seal region of afluid-containing pouch manufactured according to an ultrasonic weldingembodiment of the present invention with Primacor located between upperand lower sealing foil layers of the fluid-containing pouch. FIG. 15B isa close up cross sectional view of a region of FIG. 15A.

FIG. 16 is a micrograph of a cross-section of a seal region of afluid-containing pouch manufactured according to an ultrasonic weldingembodiment of the present invention with lacquer located between twosealing foil layers of the fluid-containing pouch.

FIG. 17 is a close-up view of a portion of the cross-section shown inFIG. 16.

FIG. 18 illustrates a laser welding system according to an alternateembodiment of the present invention.

FIG. 19 is a micrograph of a cross-section of a seal region of afluid-containing pouch manufactured according to an alternate embodimentof the present invention, using laser welding with Primacor locatedbetween two sealing foil layers of the fluid-containing pouch.

FIG. 20A is an additional micrograph of a cross-section of a seal regionof a fluid-containing pouch manufactured according to an alternateembodiment of the present invention, using laser welding with Primacorlocated between two sealing foil layers of the fluid-containing pouch.FIG. 20B is a close-up view of FIG. 20A.

FIG. 21 tabulates several parameters and improvement factors of severalseal designs according to various embodiments of the present invention.

FIG. 22 is a plot of the improvement factor tabulated in FIG. 21 foreach of several seal designs according to various embodiments of thepresent invention.

FIG. 23 illustrates a data plot of carbon dioxide (CO₂) pressure versustime for two sets of fluid-containing pouches stored at 50° C. over aperiod of about 180 days, wherein a first set of fluid-containingpouches has been sealed in a conventional manner, and wherein a secondset of fluid-containing pouches have been sealed using a methodaccording to an embodiment of the present invention.

FIG. 24 illustrates a data plot of burst strength comparing burststrength variability for the first set of fluid-containing pouches andthe second set of fluid-containing pouches.

FIG. 25 illustrates a close-up cross sectional view of a crimping regionof crimping jig according to an alternate embodiment of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The various features of the preferred embodiments will now be describedwith reference to the drawing figures, in which like parts areidentified with the same reference characters.

Introduction

The present invention will be described in terms of embodiments usefulfor the i-STAT blood testing system. However, as those of ordinary skillin the art will recognize, the present invention has broad applicabilityto other similar systems, used both in the clinical and non-clinicalenvironments, including, but not limited to, water quality testing.Extensive description of the i-STAT system is found in the followingjointly owned patents, the entireties of which are incorporated hereinby reference: U.S. Pat. Nos. 5,096,669; 5,112,455; 5,200,051; 5,614,416;6,030,827; 6,438,498; 6,750,053; and 7,263,501.

The i-STAT system comprises a hand-held reader which operates with arange of single-use disposable cartridges. Each cartridge has a siliconchip with a set of electrochemical sensors that can be used to determinethe concentration of various analytes such as, for example, sodium,potassium, glucose, creatinine, pH, oxygen, carbon dioxide, troponin I,B-natriuretic peptide and the like.

Each i-STAT cartridge also has a hermetically sealed foil pouchcontaining a fluid that is used during the analysis process, e.g., assayprocess, to provide for calibration, to react with the sample, or as awash fluid. Where the fluid is used for calibration, in the first stepthe pouch is ruptured by means of a force generated by the reader. Thefluid then flows through a conduit and into contact with the sensors.The sensors, which are in electrical contact with the reader, generate acalibrant signal that is recorded by the reader. In the second step ablood sample is forced through the conduit displacing the calibrantfluid, and signals from the sensors in contact with the blood sample arerecorded. Based on the known concentration of the analyte in thecalibrant fluid, the reader can calculate the unknown concentration ofthe analyte in the blood by means of an algorithm that uses the twosignals.

Fluid-containing pouches manufactured according to an exemplaryembodiment offer the advantage of simplifying shipping and storage ofproduct for hospitals and other users. According to an exemplaryembodiment, advanced pouch sealing techniques are employed duringformation of the pouches. In a preferred embodiment, opposing sheets ofmaterial, e.g., foil, are sealed to one another so as to fuse themtogether and form a substantially liquid and gas impermeable interfaceat the perimeter thereof. Examples of suitable sealing processes includeheat crimping, pressure crimping, heat and pressure crimping, ultrasonicwelding, metal-to-metal welding and laser welding, among other pouchsealing techniques.

Those skilled in the art will recognize that the integrity of theresulting pouch is directly dependent on the integrity of the fluid,e.g., calibrant fluid. This means that the fluid must remainsubstantially unchanged between the time it is manufactured and sealedin the pouch, and when it is used, for example in an assay. This timedifference many be many months. As a result, the sealing of the pouch iscrucial to its integrity.

Conventional Fluid-Containing Pouch Forming and Sealing

As shown in FIG. 2, each sealing foil 2 a, 2 b comprises a plastic linedside 10, and a foil side 8. According to a conventional method,illustrated in FIG. 3, jig 4 comprises a lower portion 4 a, which isgenerally concave in shape, and an upper portion 4 b, which is flat. Inthis context, the term “concave” is employed generally to refer to arecessed portion, which might not be concave in shape. Either or bothlower portion 4 a and/or upper portion 4 b includes a heating element, 6a, 6 b, respectively. A piece of sealing foil 2 a is formed in a concavemanner by lower portion 4 a of jig 4, with plastic lined side 10 of foil2 a facing away from lower concave portion 4 a. Forming of the foil intoa concave shape may be by pneumatic means, or with a vacuum chuck, or byuse of a press with a concave shape. The foil 2 a disposed in theconcave region of lower portion 4 a is then partially filled with thedesired fluid 5 (as shown in FIG. 3), e.g., calibrant fluid, and secondsealing foil 2 b is placed over the top of foil 2 a with the plasticlined side of sealing foil 2 b abutting the plastic lined side ofsealing foil 2 a (as shown in FIGS. 2 and 3). Upper portion 4 b of jig 4is then applied to the two pieces of sealing foil 2 a, 2 b to effect theseal, and heat and pressure are applied to the perimeter regions ofsealing foil 2 a, 2 b through heating elements 6 a, 6 b. As a result,the two separate plastic layers 10 a, 10 b of foils 2 a, 2 b,respectively, melt together to form a single plastic layer fusing foil 2a and foil 2 b to one another. The process effectively proceeds stepwiseas follows: (a) forming a pocket in a first plastic-lined foil, (b)depositing a liquid into the pocket, (c) covering the pocket with asecond plastic-lined foil with the plastic faces abutting one another,and (d) sealing the first and second plastic-lined foils together toform a perimeter seal, where the perimeter seal is formed by applyingsufficient heat and/or pressure to effect the perimeter seal. FIG. 4illustrates a top view of a conventionally sealed fluid-containing pouch50, showing perimeter sealing area 52 (hash marks). FIG. 7D illustratesa perspective view of a similar pouch 50.

FIG. 5 illustrates a micrograph of a cross-section of a seal region offluid-containing pouch 100 after sealing with conventional jig 4,described above. As shown, upper layer foil 2 b is in close proximity tolower foil layer 2 b, and upper and lower plastic layers 10 b, 10 a,respectively, have melted into each other to form a single continuousplastic layer 9. The micrograph shows that the plastic seal layer(comprised of upper and lower plastic layers 10 b, 10 a, of upper foillayer 2 b and lower foil layer 2 a, respectively) has a substantiallyuniform thickness across the region where the seal will occur. Asdescribed above, the fluid-containing pouches of the invention haveseals that better inhibit gas exchange from within the pouch to theambient air external to the pouch.

Improved Fluid-Containing Pouches

In some embodiments, the invention is directed to improvedfluid-containing pouches having seals that are substantially liquid andgas impermeable. For purposes of the present specification and claims, aseal is “substantially liquid and gas impermeable” if it yields a ΔpCO₂value from a Pouch Integrity Test, as defined below, of less than 30 mmHg, preferably less than 20 mm Hg, or less than 10 mm Hg. Pouches thatyield ΔpCO₂ values less than 10 mm Hg are highly desirable as theyprovide for improved pouch shelf life over conventional pouches,particularly at room temperature. In other aspects, the invention is tovarious processes for forming fluid-containing pouches.

The pouches may be formed, for example, by crimping (e.g., with heatand/or pressure), ultrasonic welding, laser welding, and/or folding amaterial in a regular undulation comprising one or more bends such thatthe material will retain the shape intended. In a preferred embodiment,the fluid-containing pouch is sealed by a crimping process in which heatand pressure are applied to seal opposing foils to one another and forma substantially liquid and gas impermeable seal. Preferably, the heat issufficient to melt the plastic and the pressure is sufficient to force aportion of the melted plastic from the seal region into the pocket,resulting in a structure where the average thickness of plastic in theperimeter seal is less than the initial combined thickness of the twoplastic linings, preferably at least 25% less, e.g., at least 50% less,at least 75% less, at least 90% less or at least 95% less than thecombined thickness of the two plastic linings prior to heating.

FIGS. 6A and 6B illustrate cross-sectional micrographs of seal regionsaccording to two exemplary embodiments of the invention. Thesemicrographs were made by cutting through the pouch and mounting it in aresin block and polishing the surface so that an image of the seal canbe recorded. Specifically, the resin, e.g., Crystalbond, is heated(˜250° C.) and placed with the component into a mold. After cooling, theresin preferably is polished, e.g., first with 800 Grit paper,progressively finer abrasives and then finally with 3 μm diamond polishuntil an optically satisfactory surface is produced. It has been foundthat dark field images give better detail and this method is used forthe images shown.

As shown in the embodiment of FIG. 6A, lower sealing foil 2 a has beensealed with upper sealing foil 2 b using crimping jig 18 (see FIG. 8) toform reduced plastic sealing region 12 (reduced in thickness), andforming interior plastic seal bead 14, the net effect of which, asdiscussed in greater detail below, provides a substantially liquid andgas impermeable seal. In the embodiment of FIG. 6B, lower sealing foil 2a has been sealed with upper sealing foil 2 b using crimping jig 18 (seeFIG. 8) to form reduced plastic sealing region 12 (reduced inthickness), and forming interior plastic seal bead 14 as well as anexterior plastic seal bead 16, to provide a substantially liquid and gasimpermeable seal. The embodiment of FIG. 6A may be formed from theembodiment of FIG. 6B, for example, by trimming the pouch (optionally inpunch station 32, described below with reference to FIG. 1) in theregion of the reduced plastic sealing region so as to remove outer bead16.

FIG. 1 is a schematic design for an automated form, fill, and sealprocess and system (pouch sealing system 150) to fill and sealfluid-containing pouches according to one embodiment of the invention.According to a preferred embodiment, sealing foils 2 a, 2 b includesaluminum foil 8 with a nominal thickness ranging from about 0.01 toabout 2.0 mm, and preferably about 0.02 to about 0.05 mm, and in thepreferred embodiment about 0.0015 inches (0.038 mm). The foil alsopreferably includes a plastic layer 10 formed thereon and having anominal thickness of from about 0.005 to about 0.5 mm, and preferablyfrom about 0.01 to about 0.05 mm, and in the preferred embodiment about0.0008 inches (0.020 mm).

The specific plastic material employed in the plastic layer may varywidely. In some exemplary embodiments, the plastic is selected frompolyvinyl chloride (PVC), polyethylene and polypropylene, e.g., DowCorning™ Primacor™ plastic liner. During manufacture, plastic layer 10preferably is extruded onto an aluminum foil roll 8. Those of ordinaryskill in the art will recognize that other lined foils can also be used,including, for example, aluminum coated with PVC or aluminum coated withpolyethylene. In addition to the use of aluminum for the foil layer,copper or brass foils or other metal foils may be used.

As shown in FIG. 1, sealing system 150 comprises several componentsincluding forming foil unwind station 20, active/passive index station(index station) 22, forming station 24, fluid dispensing station 25, lidfoil unwind station 26, seal station 28, dimple station 30, punchstation 32, and rear indexing station 33. Forming foil unwind station20, which retains and dispenses lower sealing foil 2 a, includesadjustments for various material reel widths, including guide rollers,driven rollers, and counter rubber rollers. Index station 22, whichallows for movement of sealing foil 2 a, includes a pneumatic driver ona slide table with a mechanical stop for the active index, and aspring-return passive index to keep constant tension on sealing foil 2a. Index station 22 is adjustable for both the active and passiveindexes. Forming station 24 pneumatically cold-forms the foil byapplication of high-pressure air over a shaped form (e.g., concavecrimping jig 18 a, shown in FIG. 8) or by mechanical deformation. Eithermethod forms the pocket into which fluid is dispensed in fluiddispensing station 25. The fluid dispense station 25 includes a pump andcontroller mountings. According to various embodiments, from about 0.01to about 2.0 mL of fluid may be used. In a preferred embodiment about0.1 to about 0.3 mL is used, preferably about 0.16 mL of fluid, e.g.,calibrant fluid, reactant fluid or wash fluid, is dispensed into eachpocket.

The lid foil unwind station 26 provides upper sealing foil 2 b, andincludes adjustments for various material reel widths and guide rollers.Following lid foil unwind station 26 is seal station 28. The sealcomponent of seal station 28, which forms part of crimping jig 18,includes a chilled top plate and a heated upper sealing plate (flatcrimping jig 18 b, shown in FIG. 8) and temperature controller.According to exemplary embodiments, the seal temperature depends on themelting point of the plastic that is being used and is typically in theranges from about 200° C. to about 500° C., e.g., from about 200° C. toabout 450° C. These values are readily obtained from the plasticsliterature. In the preferred embodiment using Primacor, it is preferableto use a sealing temperature of about 300 to 400° C. and for actualproduction of pouches the temperature was set at 360° C.+5° C. The sealforce is preferably initially about 900 Newtons±50 N, increasing to amaximum force of about 6,700 Newtons±230 N during the sealing cycle.Optionally, the perimeter seal is formed by applying pressure in therange of from about 5,000 lb/inch² (34.5 MN/m²) to about 9,000 lb/inch²(62.1 MN/m²), and optionally about 6,666 lb/inch² (46.0 MN/m²).

Those skilled in the art will recognize that the area of the seal willaffect the desired applied force to obtain a reliable seal. This may beascertained without undue experimentation using the methods describedherein. Fluid dispensing station 28 also preferably includes a load cellfor monitoring the sealing force.

The next component of exemplary sealing system 150 is dimple station 30.Dimple station 30 mechanically deforms one side of the sealed foil pouchcreating an indentation. The indentation preferably is in the center ofthe pocket of fluid-containing pouch 100 as shown in FIGS. 7A and 7B.FIGS. 7A-7C illustrate a top view, perspective view, and side viewrespectively of fluid-containing pouch 100 manufactured using sealingsystem 150. FIG. 7E provides an additional perspective view showingcrimped edge 101. (For comparison, FIG. 7D illustrates a conventionallysealed fluid-containing pouch lacking crimped edge 101.) A laser, notshown in FIG. 1, can be used to measure dimensions of the indentation.In the i-STAT cartridge, the purpose of the indentation is to avoidpremature contact of the puncturing element with the foil pouch.

Exemplary sealing system 150 also includes punch or cut station 32,which acts to cut out fluid-containing pouches 100 from the foil reels.Punch station 32 may include, for example, a table, guide posts, dialindicator, and adjustment screws. Furthermore, punch station 32 mayinclude delivery chutes that can discharge punched-out fluid-containingpouches 100 to a discharge conveyer at a rate, for example, ranging fromabout 10 to about 100 cycles per minute, and typically about 30 cyclesper minute. Note that where the width of the foil can accommodate morethan one pouch, the production rate will double, triple, etc. In thepreferred sealing system 150, the width of the foil accommodates threeadjacent pouches. Following punch station 32 is rear indexing station33, which may operate in a manner similar to indexing station 22.

According to a preferred embodiment, as shown in FIG. 1, two individualportions of plastic-lined sealing foil 2 a, 2 b are used to makefluid-containing pouch 100 (i.e., two separate rolls of sealing foil 2are brought together and fused to one another). In another embodiment, asingle piece of sealing foil 2 is used to manufacture fluid-containingpouches 100. According to this alternative embodiment, a single piece ofsealing foil, for example, may be folded and opposite edges sealed toform fluid-containing pouch 100.

One or more steps prior to the sealing step, e.g., the liquidapplication and sealing steps, may be performed in a controlledatmosphere in order to control the resulting gas phase compositioncontained in the pouch. For example, a glove box may be employed forthis purpose. Additionally or alternatively, the chemical composition ofthe liquid phase may be selected to substantially determine the gasphase composition after sealing. Where possible, the latter is preferredas it simplifies the overall manufacturing process. For example, abicarbonate salt can be added to the fluid and stored in a sealeddispensing container without a head space. The combined fluid andbicarbonate salt can then be dispensed into the pocket and quicklysealed. As the bicarbonate subsequently equilibrates with the air in thesmall head space in the pouch, it will determine the partial pressure ofcarbon dioxide in the fluid and head space. The equilibration ofbicarbonate is well known and follows the reaction sequence:

The above-described pouch formation process can be performed in asubstantially manual format where the foil-forming jig is separate fromthe sealing jig, and the filling step is done by manual pipetting.However, it is preferred that the process is automated, as shown in FIG.1, which depicts an automated fluid-containing pouch reel-based sealingsystem 150, wherein rolls of foil 2 a, 2 b, are continuously fed intothe form, filled and sealed. Automation enables the time between thefluid dispensing step and the sealing step to be both short (e.g.,between about 1 second to about 10 seconds) and controlled from pouch topouch.

FIG. 8 illustrates a cross-sectional view of crimping jig 18 accordingto an exemplary embodiment used in fluid dispense and sealing station28, and FIG. 9 illustrates a close-up cross sectional view of thecrimping region of crimping jig 18 as shown in FIG. 8. Crimping jig 18includes lower concave crimping jig 18 a and flat crimping jig 18 b. Asshown, crimping jig orifice 34 accepts lower sealing foil 2 a,optionally with the application of a vacuum, as it is passed over lowerconcave crimping jig 18 a from forming foil unwind station 20, indexstation 22, and forming station 24. An outside perimeter edge of lowersealing foil 2 a sits on crimping region 36. Crimping region 36, whichis shown in greater detail in FIG. 9, includes interior crimp regionedge 38, flat crimp region 40, and exterior crimp region edge 42. Asshown, an inward angled edge 39 separates interior crimp region edge 38and flat crimp region 40. During pressing, inward angled edge 39facilitates inward migration of melted plastic from the region of flatcrimp region 40 toward interior crimp-region edge 38. Additionally oralternatively, the crimping region may include an outer angled edge (notshown) separating flat crimp region 40 from exterior crimp region edge42, which outer angled edge facilitates outward migration of meltedplastic from the region of flat crimp region 40 toward exterior crimpregion edge 42.

Although FIG. 8 illustrates crimping region 36 as a part of lowerconcave crimping jig 18 a, in another embodiment (not shown), thecrimping region is a part of the upper crimping jig, and the perimeterregion of lower concave crimping jig is substantially flat. In anotheraspect (not shown), both the upper and lower crimping jigs includecrimping regions (i.e., neither upper or lower crimping jig includes asubstantially flat region at the periphery thereof).

FIG. 10 illustrates crimping region 36 with lower sealing foil 2 aplaced against lower concave crimping jig 18 a, and after orifice 34 hasaccepted sealing foil 2 a, but before upper sealing foil 2 b and upperflat crimping jig 18 b have been pressed against lower sealing foil 2 aand lower crimping jig 18 a. Ultimately, force is applied by pressingupper flat crimping jig 18 b and upper sealing foil 2 b against lowersealing foil 2 a and lower crimping jig 18 a, preferably in the presenceof heat (either or both lower concave crimping jig 18 a and/or upperflat crimping jig 18 b may be heated) to form crimped fluid-containingpouch 100. As indicated above, the plastic sides of foil 2 a, 2 bpreferably are facing or abutting one another such that the plastic fromfoil 2 a and foil 2 b are melted into one another and migrate inwardlyand/or outwardly from flat crimp region 40 to form interior and/orexterior plastic seal beads, respectively.

The width (W) of flat crimping region 40 may vary widely. Severaldifferent design variations (A-H) were tested to determine the impactthat the width of flat crimp region 40 had on the ability offluid-containing pouch 100 to withstand CO₂ in-gassing. Several designdimensions, A, B, C, and D, are shown in FIGS. 7A-7C. The designparameters for test designs A-H are provided in FIG. 21. In oneembodiment, the difference between dimension A and B provides the widthof flat crimp region 40 on two sides of fluid-containing pouch 100([A−B]/2 for a single side), and the difference between dimensions C andD provide the width of flat crimp region 40 on the other two sides offluid-containing pouch 100. In other aspects, the flat crimping region40 is less than the difference between dimension A and B on two sides offluid-containing pouch 100 (e.g., from 10 to 90 percent less, from 25 to75 percent less, or from 45 to 55 percent less than the differencebetween dimensions A and B), and is less than the difference betweendimensions C and D on the other two sides of fluid-containing pouch 100(e.g., from 10 to 90 percent less, from 25 to 75 percent less, or from45 to 55 percent less than the difference between dimension C and D). Inthose aspects in which the crimped region is less than the differencebetween dimensions A and B and/or dimensions C and D, the crimpingregions preferably are centered between dimensions A and B or dimensionsC and D, respectively. The results are tabulated in FIG. 21, are showngraphically in FIG. 22, and are discussed in greater detail below. FIG.21 also tabulates the sealing area, in inches squared, which is afunction of the A, B, C, and D dimensions.

FIG. 5 illustrates a micrograph of a cross-section of a seal region of aconventional fluid-containing pouch 100 after heat pressing. Themicrograph shows that plastic seal region 12 has a substantially uniformthickness across the seal. The effect of the crimping step according toan exemplary embodiment of the invention, in contrast, is shown in themicrographs of FIGS. 6A & 6B. As shown, some of the plastic 10 of boththe upper and lower sealing foil 2 has been extruded from seal region 12into the interior of fluid-containing pouch 100, i.e., away from crimpedregion 36, to form an interior plastic seal bead 14. Note also that theimages clearly show that after crimping, the plastic layer in crimpedregion 36 is substantially reduced in thickness, as it is forced towardsboth the outer edge of the crimped region 36 and the interior of thecrimped region 36. The thickness of the seal in the crimped region mayvary widely, but in some exemplary embodiments ranges from 2 to 30 μm,e.g., from 2 to 20 μm or from 2 to 10 μm. In those embodiments in whichthe thickness varies across the crimped region, these ranges refer tothe average thickness across the crimped region.

In the embodiments shown in FIGS. 6A & 6B, the initial manufacturedthickness of plastic layer 10 on each layer of sealing foil is about0.0008 inches (or about 0.020 mm or 20 μm). Thus, the average thicknessof the plastic prior to crimping is in the range of about 0.0016 inchesor 40 μm taking into account both foil 2 a and foil 2 b. After crimping,the plastic seal region 12 preferably has an average thickness in therange of from about 1 μm to about 10 μm, from about 3 μm to about 7 μm,or preferably about 5 μm. Thus, this embodiment of the inventionsubstantially reduces the cross-sectional plastic area of the entireseal by a significant factor. In a preferred embodiment, the total sealwidth is about 2 mm and the length of the seal perimeter isapproximately 75 mm.

Many different crimping patterns may be employed in various embodimentsof the invention. The effectiveness of the seals resulting from severalexemplary test patterns are shown in FIG. 21. The various designs A-Hhad different selected sealing surfaces. Note that these pouch designshad an overall rectangular shape, as shown in FIGS. 7A-7C. As a result,the inner and outer seals of the long and the short axes of therectangular designs have specified dimensions. For each of the designsA-H, a batch of pouches, each containing a calibrant fluid, was preparedfor testing gas exchange. The Pouch Integrity Test (PIT) system andmethod are described in greater detail below.

Pouch Integrity Test

FIGS. 11A and 11B illustrate gas control storage vessel 44 used to storefluid-containing pouches in a controlled gas environment for an extendedperiod of time at a controlled temperature for the purpose of conductingthe PIT, and FIG. 12 illustrates a disassembled view of gas controlstorage vessel 44 as shown in FIGS. 11A and 11B. Storage vessel 44comprises sealable metal box 45 with gas inlet port 46 and gas outletport outlet 48. The storage vessel 44 enables incubation offluid-containing pouches under controlled conditions, e.g., temperature,pressure and external gas composition prior to testing. Fluid-containingpouches placed in the storage vessel 44 can be incubated for differenttime periods and then tested to determine the amount of gas exchangethat has occurred through the seal. In the PIT, calibrant pouches areruptured with a capillary tube or syringe and the contents introducedinto a chemical analysis system, e.g., a commercial blood gas analyzeror clinical chemistry analyzer. Those skilled in the art will recognizethat commercial blood gas analyzers test for pO₂, pCO₂ and pH, and havesample introduction ports that can accommodate samples delivered bymeans of a capillary tube or syringe barrel. Note that the PIT is notdependent on a specific apparatus for determining gas composition. Theimportant factor is that the testing means provide a reliable way ofdetermining the dissolved gas composition of a sample before and afterincubation in vessel 44. Furthermore it is recognized that as thepouches are single-use disposable components, it is necessary to make abatch of pouches in the same manner and then test portions of the batchat different stages of the PIT process to determine the overallperformance of the seal design through time.

The PIT was performed as follows. Fluid-containing pouches are placedinto storage vessel 44, ensuring that the samples are not covering gasinlet port 46 and gas outlet port 48 on the inside of storage vessel 44.O-ring 56 is then cleaned and placed in o-ring groove 58, verifying thatthe area and o-ring 56 are free of any contaminants that might prevent aproper seal. Lid 54 of storage vessel 44 is then sealed to sealablemetal box 45 using the supplied hardware, where six bolts 64 aretightened in a cross pattern. Inlet valve 60 and outlet valve 62 onstorage vessel 44 are then opened, and inlet valve 60 is connected to aCO₂ gas cylinder (not shown). A flow of CO₂ gas, preferably at least tentimes the volume of storage vessel 44, is used to flood storage vessel44 for a minimum of about 15 minutes. Finally, inlet valve 60 is closedand then outlet valve 62 is closed. Storage vessel 44 is then stored inthe desired test environment, e.g., at a controlled temperature.

In the PIT described herein, each fluid-containing pouch contained thefollowing: 160 μL of an aqueous solution containing glucose (90 mg/dL),urea (4.0 mM), sodium (118 mM), potassium (4.0 mM), chloride (100 mM),calcium (1.5 mM) and lactate (2.0 mM) in 47 mM HEPES buffer at pH 7.3.Of course, other fluids may be employed and analyzed under the PITdepending on the specific purpose of the pouch to be tested. Sufficientbicarbonate was also present to give an initial pCO₂ of 28 mm Hg, wherethe gas phase in the pouch is about 100 μL. In the PIT, the pouch isstored in the above-described incubation vessel at 1 atmosphere ofcarbon dioxide for a period of 8 days. The experiments were performed ata temperature of 50° C. The initial pCO₂ in the pouches was measured andthe pCO₂ in the pouches were again measured at the end of theexperiment. Typically, the pCO_(2(initial)) is determined by bursting afirst pouch with a capillary, and the pCO_(2(end)) is determined in thesame manner but from a second pouch formed in the same batch as thefirst pouch. The difference between the pCO_(2(initial)) andpCO_(2(end)) provides a ΔpCO₂ value, which is indicative of pouchintegrity, with lower ΔpCO₂ values reflecting less gas exchange and,hence, a better seal.

Each of the proposed designs were assessed in an accelerated testingmode using the incubation vessel described above. Several samples offluid-containing pouches (A-H) were placed in the incubation vessel at 1atmosphere of carbon dioxide and stored for a period of 8 days. Theexperiments were performed at a temperature of 50° C. The initial pCO₂in the pouches was measured (generally about 28 mm Hg) and the pCO₂ wasagain measured at the end of the experiment. For the standard process,with conventional seals, the final pCO₂ was about 60 mm Hg. This was dueto ingress of CO₂ through the seal, as described above. This 32 mm HgΔpCO₂ value was used as a baseline result against which the variouscrimping designs were tested. The table in FIG. 21 lists an ImprovementFactor, which is defined herein as ΔpCO₂ for the standard processdivided by the ΔpCO₂ for the new process. For design A, the ΔpCO₂ valuewas much less than the 32 mm Hg observed for the standard process,giving an improvement factor of 4.8. Improvement factors for otherdesigns are listed in FIG. 21 and shown graphically in FIG. 22, withdesign E providing the best result. Design E was used in the testingdescribed immediately below.

Long-Term Stability Studies

The next set of experiments were designed to indicate the long-termperformance of design E under normal storage conditions, i.e., ambientair either refrigerated or at room temperature. These experiments werealso performed in an accelerated mode, i.e., by storing the test sampleat 50° C. Those skilled in the art will recognize that satisfactoryresults obtained in the accelerated mode should be indicative of similaror (more likely) better performance at ambient or refrigeratedtemperatures as gas permeability of plastics generally increases withtemperature.

The head-space or gas phase in fluid-containing pouch 100 of design Ehas a volume of about 100 μL, and the partial pressure of CO₂ withinfluid-containing pouch 100 was similar to that found in a blood sample,e.g., about 28 mm Hg. In contrast, the CO₂ concentration in ambient airis about 0.03%, or about 0.24 mm Hg. This is substantially less and thusthe driving force is for CO₂ loss from fluid-containing pouch 100. Thedriving force is based on the law of mass action; the net process willbe for CO₂ to slowly diffuse out through the plastic seal and exit thefluid-containing pouch 100. Those skilled in the art will recognize thattests similar to the PIT experiments, discussed above, can be performedwith ambient air instead of carbon dioxide gas. Using carbon dioxide at1 atmosphere (760 mm Hg) provides a driving force for ingress of CO₂,whereas ambient air provides a driving force for egress. Both canprovide information about the seal integrity, however the PIT uses acarbon dioxide atmosphere as it is easier to measure an increase inpouch pCO₂ and also results are obtained more quickly due to the greaterdriving force. Note that an elevated temperature is used to increase therate of gas transport, with the intention of observing a demonstrabledifference between the two types of pouches, e.g., crimped according toan exemplary embodiment, and a conventionally sealed fluid-containingpouch 50.

To determine any change in the internal initial partial pressure of CO₂of fluid-containing pouch 100, a subset of fluid-containing pouches 100were intermittently tested. Specifically, at times of 0, 30, 60, 90,120, 150, and 180 days, both fluid-containing pouches 100 andconventional fluid-containing pouches 50 were removed from the ambientair incubator at 50° C. and tested. This was done by assembling theminto i-STAT EG7+ cartridges and testing the resulting partial pressureof carbon dioxide (pCO₂) versus a tonometered control fluid at a pCO₂ of28 mm Hg. Note that pCO₂ is a standard test offered by the i-STAT systemusing an electrochemical pCO₂ sensor.

For background, it is important to note that the test algorithm in thei-STAT reader assigns a value of 28 mm Hg to the signal recorded in thecalibration fluid. This is a factory calibration process, where thereader is pre-programmed with software that assumes the calibrant fluidpCO₂ value will be 28 mm Hg, and fluid-containing pouches 100 aremanufactured with a fluid composition that is intended to be 28 mm Hg.Once a batch of fluid-containing pouches 100 were made and assembledinto test devices, a statistically valid sample of the batch was testedto determine whether the intended pCO₂ value is actually observed. Ifso, the batch of fluid-containing pouches 100 can be assembled intocartridges and then shipped to customers.

Consequently, if the calibrant fluid and the tonometered fluid in theexperiment both have a concentration of about 28 mm Hg, then this willbe the reported value (see data points in FIG. 23). However, if CO₂ hasbeen lost from fluid-containing pouch 100 and the actual value is, forexample, 10 mm Hg, because the reader will assign the pre-programmed 28mm Hg value to the signal from the calibrant fluid, when the sensor ischallenged with a tonometered sample that is actually 28 mm Hg, thereported value will be higher. The degree to which the reported value ishigher than 28 mm Hg is a measure of how much CO₂ has been lost from thepouch during storage.

FIG. 23 illustrates a data plot of carbon dioxide (CO₂) partial pressureversus time for two sets of fluid-containing pouches stored at 50° C.over a period of about 180 days, wherein a first set of fluid-containingpouches 50 has been sealed in a conventional manner, and a second set offluid-containing pouches has been crimped using a method according to anexemplary embodiment (design E) of the invention. In FIG. 23, thediamonds represent pCO₂ values for fluid-containing pouches of design E,and the squares represent pCO₂ values for conventional fluid-containingpouches 50, both of which were stored at 50° C., with a calculatedlinear fit through the data points. Initially, the pCO₂ in both sets ofpouches read about 28 mm Hg. However, after 180 days, the PCO₂ in thestandard pouches had fallen sufficiently to cause the tonometered fluidsample to read about 47 mm Hg, whereas fluid-containing pouchesmanufactured according to design E have only changed slightly to readabout 31 mm Hg.

This is a surprising, unexpected and significant result since thecrimping step could have been expected to have a deleterious effect onthe seal despite narrowing the seal cross-section. For example, thecreation of microscopic fissures in either of both of plastic layer 10or foil layer 8 sealing foil 2 would be expected to decrease pouchperformance. As a result, is has been surprisingly found that thecrimping feature substantially improves the seal by reducing gasexchange.

As described above, it will also be apparent that CO₂ loss mayalternatively be determined by rupturing a fluid-containing pouch 100(or conventional fluid-containing pouch 50) and filling a glasscapillary tube with a portion of the fluid in the fluid-containingpouch. The fluid is then transferred to a standard bench-top blood gasanalyzer, where the fluid is injected and a pCO₂ result is reported bythe analyzer. In these experiments, it was also shown that thefluid-containing pouches of design E had a substantially unchanged pCO₂value after 180 days at 50° C., whereas conventional fluid-containingpouches 50 exhibited a loss of CO₂.

Burst Strength Tests

The conclusions based on the data in FIG. 23 were confirmed by separateexperiments on the burst strength of fluid-containing pouch 100. In theburst strength test, a different jig was used to determine the forcerequired to burst fluid-containing pouch 100, i.e., cause destructivefailure of the seal. In circumstances where the crimping causes damageto the seal, this would result in a more variable burst strength of theseal. As shown in FIG. 24, while the burst strength of conventionalfluid-containing pouch 50 is higher (averaging 551.7 N with n=102 and astandard deviation of 66.1 (12%)), it is more variable thanfluid-containing pouch 100 according to an exemplary embodiment design E(averaging 307.2 N with n=105 and a standard deviation of 30.7 (10%)).It was found that the more consistent burst strength, i.e., lowerabsolute variation, of design E of fluid-containing pouch 100 isindicative of a more reliable and reproducible process. Note that thelower burst strength is indicative of the reduced amount of Primacommadhesive in the seal region.

As described above, FIG. 21 illustrates a table showing differentcrimping designs, where design E corresponds to a preferred embodimentof fluid-containing pouch 100. These results also indicate that thecrimping process can yield an improved and viable manufacturing processsuitable for high volume demand. A desirable crimp design is one inwhich the gap between foil layers is substantially minimized. However,the crimp must not disrupt the integrity of the polymer (plastic) liner10 of sealing foil 2 due to the potentially corrosive nature of thefluid contained within fluid-containing pouch 100 and its interactionwith aluminum layer 8. Nor should the crimp cause fissures or otherdamage to aluminum layer 8.

Through further experimentation and design it was found that thefollowing features reflect preferred embodiments for fluid-containingpouches. According to a preferred embodiment, the two portions ofsealing foil 2 are rectangular, e.g., 1.5 cm×2.2 cm, with an area ofabout 3.3 cm². It was found that useful foil areas can range from about0.5 cm² to 20 cm².

According to a preferred embodiment, the volume of the enclosure offluid-containing pouch 100 is about 100 to 300 μL, however pouches withinternal volumes in the range of about 5 μL to about 5 mL may be used.Thus, the volume of the liquid phase in the enclosure can be in therange of about 5 μL to about 5 mL. Likewise, the volume of the gas phasein the enclosure can be in the range of from about 5 μL to about 5 mL.

According to a preferred embodiment, the volume of the liquid phase inthe enclosure is about 50% to 95%, e.g., from 60% to 65% of the totalvolume of the enclosure. In addition, the volume of the gas phase in theenclosure can be in the range of about 5% to about 50% of the volume ofthe enclosure.

According to a preferred embodiment, a portion of plastic layer 10 isforced by the act of sealing and crimping into the enclosure, and formsinterior plastic seal bead 14 along at least a portion of the interiorperimeter of the seal, as shown in FIGS. 6A & 6B. This processaccommodates the plastic that is lost from the seal region duringsealing and crimping. As can be seen in FIGS. 5 and 6, the averagethickness of plastic in the perimeter seal is substantially less, and atleast 20% less than the original combined thickness of the two plasticlayers 10.

According to a preferred embodiment, the perimeter seal has a perimeterwidth (or gas diffusion path-length) of less than about 20 mm, e.g.,less than about 10 mm or less than about 5 mm. In terms of ranges, theperimeter seal optionally has a width of from about 1 mm to about 20 mm,and most preferably about 2 mm to about 3 mm. The perimeter widthpreferably is equal to or less than the length defined by half A minusB, or half C minus D, as shown in FIG. 7A. The specific perimeter widthtypically will be determined by the width of the crimping region. Inaddition, according to the preferred embodiment, the perimeter seal hasa perimeter length of from about 1 cm to about 20 cm, and mostpreferably from about 7 cm to about 8 cm, as shown in FIG. 7A, i.e., thelength defined by 2A plus 2C.

While a preferred embodiment of an apparatus for crimpingfluid-containing pouch 100 is shown in FIGS. 8 and 9, the crimpedfeature may also be comprised of multiple concentric crimping rings,wherein the rings may number from, for example, from 2 to 10 crimpingrings. In this context, the term “rings” and “concentric” is not limitedto circular shapes, as square or rectangular crimped features arepreferred. Typically these will have rounded corners. For example,referring to FIG. 9, flat crimp-region 40 can be divided evenly intofive parts, wherein an inner, outer and central portion are of the sameheight as depicted for flat crimp-region 40, with the two other portionson either side of the central portion having the height depicted forregion 52. This configuration is shown in FIG. 25, and acts to formthree concentric crimping rings. As shown, the rings are formed frompeaks 40 a, 40 b, and 40 c, and are separated by gaps corresponding tovalleys 42 a, 42 b and 42 c. Of course, many other patterns maysimilarly be formed by varying the number and/or widths of the peaks.

Exemplary fluid-containing pouches manufactured in accordance with theinventive principles discussed and described herein have provensuccessful in calibrating blood testing sensors. In addition, thefluid-containing pouches of the invention exhibit an extended shelf-lifewith refrigeration, and also remained substantially unaltered withextended room temperature storage, e.g., six months. Thefluid-containing pouches of the invention preferably have a roomtemperature shelf life greater than 3 months, greater than 6 months,greater than 9 months or greater than 1 year. As a result, thefluid-containing pouches of the invention offer the advantage ofsimplifying shipping for the manufacture of test cartridges containingthe inventive fluid-containing pouches, and also simplifying storage ofcartridges for hospitals and other users.

According to an alternate exemplary embodiment, fluid-containing poucheshaving a substantially liquid and gas impermeable seal can bemanufactured using an ultrasonic welding machine 66, shown in FIG. 13.Those of ordinary skill in the art will recognize that polymers may becharacterized by their gas transmission rate and therefore arenon-hermetic materials. It is therefore also considered advantageous toobtain metal-to-metal sealing as metals, e.g., aluminum, in the absenceof pinholes are generally impervious to gases. The advantages ofmetal-to-metal sealing needs to be balanced, however, against possibleinteractions of the calibrant fluid with the metal, as described above.The use of an intervening inert polymer layer obviates this potentialproblem.

At least two additional types of sealing foil can be used withultrasonic welding machine 66 according to various exemplaryembodiments: the first is the Primacor-coated aluminum foil of the typedescribed above (i.e., sealing foil 2, with foil layer 8 and plasticlayer 10), and the second is a lacquer-coated sealing foil (sealing foil2′, with foil layer 8 and lacquer layer 11). According to an exemplaryembodiment, it is desirable to have lacquer layer 11 present on foillayer 8 to avoid direct contact between the calibrant fluid and thealuminum. The lacquer may comprise, for example, one or more ofnitrocellulose, urea and acrylic resins, and may be applied, forexample, by printing. The quantity of lacquer applied is generally about0.1 to about 10 g/m² and preferably about 1.5 g/m².

FIG. 13 illustrates welding machine 66 according to an exemplaryembodiment. Ultrasonic welding is achieved by application of pressure toparts held between stationary multi-ridged plate 70 and mobilemulti-ridged plate 68, which vibrates at an ultrasonic frequency. Theaction of rubbing the stationary part of sealing foil 74 against themobile part of sealing foil 72 causes oxides to be dispersed allowingmetal-to-metal bonding to occur. Of course, in other embodiments, thelower plate may vibrate instead of or in addition to the upper plate.

FIG. 14 illustrates a micrograph of a seal region formed using sealingfoil 2 having a plastic layer (formed of Primacor™) and formed from anultrasonic welding machine having ridged plates. FIG. 14 shows that the38 μm upper sealing foil 2 b and lower sealing foil 2 a above and belowthe seal are undamaged, and that a contiguous layer of Primacor (ofvariable thickness 5-30 μm) remains. The seal shown in FIG. 14 has afirst plastic region 76 and a second plastic region 78, which is thickerthan the first plastic region. FIGS. 15A & 15B show a micrograph of asimilar seal region also formed by ultrasonic welding and having a firstplastic region 76 with a plastic layer that is about 5 μm thick and asecond plastic region 78 having a plastic layer that is about 15 μmthick. According to an exemplary embodiment, substantially no directmetal-to-metal contact or bonding occurs even in the thinner regions, asshown in region 82 of FIGS. 15A & 15B. Specifically, region 82represents a region where the thickness of plastic layers 10 a, 10 b isabout 10 μm. Region 80 represents a region where the thickness ofplastic layers 10 a, 10 b is about 30 μm.

FIG. 16 is a micrograph of the seal region formed with by ultrasonicwelding of sealing foils having abutting protective lacquer layers. Theembodiment shown is formed from an ultrasonic welding machine havingsubstantially flat plates. FIG. 16, and especially FIG. 17, which is aclose-up of the seal region shown in FIG. 16, shows that there is aminimal gap between upper sealing foil layer 2 a, and lower sealing foillayer 2 b, and that in some regions, there is metal-to-metal contact, asshown in region 81 of the enlarged view in FIG. 17.

Thus, according to exemplary embodiments, it is evident that seals madeby ultrasonic welding machine 66, as with crimping seals made bycrimping jigs 18 a, b, can also advantageously minimize or eliminate gasexchange between the interior of the fluid-containing pouch and theexterior ambient air.

In another embodiment, the substantially liquid and gas impermeable sealis formed by a laser welding system. FIG. 18 illustrates laser weldingsystem 84. Laser welding can also be usefully applied to sealfluid-containing pouches using a Primacor-coated sealing foil or alacquer-coated sealing foil. Laser welding is achieved by placing twosheets, e.g., foil, in intimate contact followed by application of asufficiently high power density of laser light (approximately 107watt/inch² for aluminum) to cause melting of the materials. A laserwelding system 84 for welding thin materials, such as polymer-coatedsealing foils, is depicted in FIG. 18. In this depiction, laser optics86 are used to focus laser light, using laser optic guide 88, to asufficiently high energy density to cause melting of both upper sealingfoil 2 b, and lower sealing foil 2 a. Alternative weld geometries arealso possible with laser welding, for example, to form abutted or T-weldjoints.

According to a preferred embodiment, laser welding machine 84 achieveshermetic laser welding of sealing foil 2 a, 2 b with a pulsed neodymiumYAG laser coupled via laser optics 86 and laser optics guide 88. Thelaser pulse width is approximately 1.5 milliseconds in duration and theenergy delivered per pulse is about 1.0 Joule. A continuous weld (orseal) can be achieved by overlapping of the laser pulses by translatingthe assembly, i.e., the position of sealing foil 2 a, 2 b relative tolaser welding machine 84, at a rate, for example of about 1-20 mm/s,preferably 5 mm/s.

In order to demonstrate that laser welding machine 84 can generate ametal-to-metal seal using the Primacor-coated seal foil 2 (i.e., sealingfoil 2 with foil layer 8 and plastic layer 10), sealing foil layers 2 a,2 b were inverted so that foil layers 8 a, 8 b abutted each other. FIG.19 is a micrograph of the seal region, and illustrates that there is nogap between upper and lower sealing foil layers 2 b, 2 a and ametal-to-metal bond is formed at laser sealed region 90. FIG. 20Aprovides an additional micrograph of one side of a weld having lasersealed region 90, and FIG. 20B shows a close-up view of a region of FIG.20A. As mentioned previously, a full metal-to-metal seal is highlydesirable as it eliminates the opportunity for gas exchange through aplastic seal and hence forms a substantially liquid and gas impermeableseal. Note that the metal-to-metal bond can also be formed by abuttingthe foil layers with plastic layers together, and performing the laserwelding process. Here, the plastic in the seal region is preferablyvaporized to allow for metal-to-metal bond formation.

According to an alternate embodiment, full metal-to-metal sealedfluid-containing pouches 100 can be manufactured in which the fluidcontained is entirely encapsulated within polymer provided thatpatterned polymer-on-foil is available. Polymer patterned foil can beproduced by either spatially controlled addition of polymer to foil orby selective removal of polymer from an entirely polymer-coated foil.Examples of methods that may be used to allow for spatially controlledaddition of polymer to foil include printing, photolithography, andlamination. Selective removal of polymer from an entirely polymer coatedfoil can be achieved by laser ablation. For continuous manufacture ofsuch pouches an important process control issue is the alignment of thetop and bottom patterned foil parts. One method whereby consistentalignment may be achieved is though the use of indexed stock material onreels.

According to a further alternate embodiment, full metal-to-metal sealedfluid-containing pouches 100 can be manufactured in which the interiorfluid is entirely contained within polymer by first sealing a polymerpouch containing the fluid and then seal that container within ahermetic metal-to-metal sealed pouch. A polymer pouch can be produced bythermally sealing and severing a segment of polymer tubing filled withfluid. These polymer pouches can then be placed appropriately forsealing within a foil pouch.

The present invention has been described with reference to certainexemplary embodiments thereof. However, it will be readily apparent tothose skilled in the art that it is possible to embody the invention inspecific forms other than those of the exemplary embodiments describedabove. This may be done without departing from the spirit and scope ofthe invention. The exemplary embodiments are merely illustrative andshould not be considered restrictive in any way. The scope of theinvention is defined by the appended claims and their equivalents,rather than by the preceding description. All United States patents andapplications, foreign patents, and publications discussed above arehereby incorporated herein by reference in their entireties.

1. A fluid-containing pouch, comprising: first and second opposingsheets; and a fluid disposed between the first and second opposingsheets, wherein the first sheet and the second sheet have asubstantially liquid and gas impermeable perimeter seal at least aportion of which has a seal width less than about 4 mm, and wherein thepouch yields a Pouch Integrity Test ΔpCO₂ value of less than about 10 mmHg.
 2. The fluid-containing pouch of claim 1, wherein the first sheetand the second sheet are folded in an undulating pattern having aplurality of bends.
 3. The fluid-containing pouch of claim 1, whereinthe first sheet includes a first foil layer and a first plastic layer,and the second sheet includes a second foil layer and a second plasticlayer.
 4. The fluid-containing pouch of claim 3, further comprising: aninterior plastic seal bead disposed at an interior edge of the perimeterseal.
 5. The fluid-containing pouch of claim 3, wherein the first sheetincludes a first foil layer and a first plastic layer, and the secondsheet includes a second foil layer and a second plastic layer, andwherein the perimeter seal comprises a third plastic layer disposedbetween the first and second foils and having an average thickness lessthan the combined thickness of the first and second plastic layers. 6.The fluid-containing pouch of claim 5, wherein the third plastic layerhas an average thickness that is at least about 25% less than thecombined thickness of the first and second plastic layers.
 7. Thefluid-containing pouch of claim 5, wherein the third plastic layer hasan average thickness that is at least about 50% less than the combinedthickness of the first and second plastic layers.
 8. Thefluid-containing pouch of claim 5, wherein the first and second foillayers have a thickness in the range of from about 0.01 to about 2.0 mm.9. The fluid-containing pouch of claim 5, wherein the first and secondplastic layers have a thickness in the range of from about 0.005 toabout 0.5 mm.
 10. The fluid-containing pouch of claim 5, wherein thefirst and second plastic layers comprise plastic selected from the groupconsisting of Primacor, polyvinyl chloride, polytethylene and lacquerbased on nitrocellulose, urea and acrylic resins.
 11. Thefluid-containing pouch of claim 5, wherein the first and second plasticlayers are substantially rectangular and have respective areas in therange of from about 0.5 cm² to about 20 cm².
 12. The fluid-containingpouch of claim 5, further comprising a plastic bead along at least aportion of the perimeter seal.
 13. The fluid-containing pouch of claim5, wherein the perimeter seal is formed by applying heat in the range offrom about 200° C. to about 500° C.
 14. The fluid-containing pouch ofclaim 5, wherein the perimeter seal is formed by applying pressure inthe range of from about 34.5 MN/m² to about 62.1 MN/m².
 15. Thefluid-containing pouch of claim 5, wherein the perimeter seal has aperimeter width of from about 1 mm to about 2 cm.
 16. Thefluid-containing pouch of claim 5, wherein the perimeter seal has aperimeter length of from about 1 cm to about 20 cm.
 17. Thefluid-containing pouch of claim 1, wherein the first sheet includes afirst foil layer and a first lacquer layer, the second sheet includes asecond foil layer and a second lacquer layer, and the first and secondfoil layers are fused to one another at the perimeter seal.
 18. Thefluid-containing pouch of claim 1, wherein the fluid is a calibrantfluid containing a known concentration of one or more analytes.
 19. Thefluid-containing pouch of claim 1, wherein the fluid is a reactantfluid.
 20. The fluid-containing pouch of claim 1, wherein the fluid is awash fluid.
 21. The fluid-containing pouch of claim 1, wherein the pouchhas a burst strength standard deviation of less than 12%.
 22. Thefluid-containing pouch of claim 1, wherein the first sheet and thesecond sheet, respectively, are opposing folded portions of a singleplastic-lined foil.
 23. The fluid-containing pouch of claim 1, whereinthe first sheet and the second sheet, respectively, are two separatepieces of foil.
 24. The fluid-containing pouch of claim 1, wherein thefirst sheet and the second sheet comprise a metallic foil selected fromthe group consisting of aluminum foil, copper foil and brass foil. 25.The fluid-containing pouch of claim 1, wherein the first sheet and thesecond sheet comprise foil with a thickness in the range of from about0.01 to about 2.0 mm.
 26. The fluid-containing pouch of claim 1, whereinthe pouch has a pouch volume of from about 5 μL to about 5 mL.
 27. Thefluid-containing pouch of claim 26, wherein the pouch contains a liquidhaving a liquid volume of from about 5 μL to about 5 mL.
 28. Thefluid-containing pouch of claim 27, wherein the liquid volume is fromabout 50% to about 95%, based on the total pouch volume.
 29. Thefluid-containing pouch of claim 26, wherein the pouch contains a gasvolume of about 5 μL to about 5 mL.
 30. The fluid-containing pouch ofclaim 29, wherein the gas volume is from about 5% to about 50%, based onthe total pouch volume.
 31. The fluid-containing pouch of claim 29,wherein the gas in the gas phase comprises a calibrant gas having aknown concentration or partial pressure of one or more gases.
 32. Thefluid-containing pouch of claim 29, wherein the gas in the gas phase isambient air.
 33. The fluid-containing pouch of claim 1, wherein theperimeter seal includes one or more crimped regions.
 34. Thefluid-containing pouch of claim 33, wherein the one or more crimpedregions comprise multiple concentric crimping rings.
 35. Thefluid-containing pouch of claim 1, wherein the pouch is in a cartridgecontaining a sensor.
 36. The fluid-containing pouch of claim 1, whereinthe pouch contains a calibrant fluid used to calibrate a sensor.
 37. Thefluid-containing pouch of claim 1, wherein the pouch contains acalibrant fluid with a predetermined partial pressure of carbon dioxide,the calibrant fluid being used to calibrate a sensor for the partialpressure of carbon dioxide.
 38. The fluid-containing pouch of claim 1,wherein the pouch is in a single-use cartridge containing at least onesensor, and wherein the cartridge is used in conjunction with a readerto measure an analyte is a sample.
 39. A fluid-containing pouch,comprising: first and second opposing sheets; and a fluid disposedbetween the first and second opposing sheets, wherein the pouch has aburst strength with a standard deviation of less than 12%.
 40. A methodfor forming a fluid-containing pouch, comprising the steps of: (a)depositing a fluid on a first sheet; (b) positioning a second sheetopposite the first sheet; and (c) sealing the opposing first and secondsheets to one another and forming a sealed region having the fluidcontained therebetween, wherein the sealed region is substantiallyliquid and gas impermeable.
 41. The method of claim 40, wherein thepouch yields a Pouch Integrity Test ΔpCO₂ value of less than 10 mm Hg.42. The method of claim 40, wherein the sealed region comprises a sealedperimeter region.
 43. The method of claim 40, wherein the sealingcomprises applying heat and pressure to the first sheet and secondsheets.
 44. The method of claim 40, wherein the sealing comprisesultra-sonic welding.
 45. The method of claim 40, wherein the sealingcomprises laser welding.
 46. The method of claim 40, wherein the firstsheet and the second sheet are folded in a undulating pattern having aplurality of bends.
 47. The method of claim 40, wherein the first sheetincludes a first foil layer and a first plastic layer, and the secondsheet includes a second foil layer and a second plastic layer, andwherein the step of sealing comprises melting the first plastic layer onthe first sheet with the second plastic layer on the second sheet suchthat an interior plastic seal bead is formed, and wherein the interiorplastic seal bead substantially prevents the calibrant liquid fromcontacting either of or both of the first and second foil layers. 48.The method of claim 40, wherein the first sheet includes a first foillayer and a first plastic layer, and the second sheet includes a secondfoil layer and a second plastic layer, and wherein the perimeter sealcomprises a third plastic layer disposed between the first and secondfoils and having an average thickness less than the combined thicknessof the first and second plastic layers.
 49. The method of claim 40,wherein the third plastic layer has an average thickness that is atleast about 50% less than the combined thickness of the first and secondplastic layers.
 50. The method of claim 40, wherein the third plasticlayer has an average thickness that is at least about 25% less than thecombined thickness of the first and second plastic layers.
 51. Themethod of claim 40, wherein the first sheet includes a first foil layerand a first lacquer layer, and the second sheet includes a second foillayer and a second lacquer layer, and wherein the step of sealingcomprises ultrasonic welding the first foil layer to the second foillayer.
 52. The method of claim 40, wherein the fluid is a calibrantfluid.
 53. The method of claim 40, wherein the fluid is a reactantfluid.
 54. The method of claim 40, wherein the fluid is a wash fluid.55. The method of claim 40, wherein the pouch has a burst strengthstandard deviation of less than 12%.
 56. The method of claim 40, whereinthe process further comprises forming a cavity in the first sheet, anddepositing the fluid in the cavity.
 57. The fluid-containing pouchformed by the method of claim
 40. 58. A substantially gas-tight sealformed with plastic-lined foil, comprising: two portions ofplastic-lined foil with plastic faces abutted where adjacent portionsare sealed together to isolate a first phase from a second phase, wheresaid seal is formed by applying sufficient heat and pressure to melt theplastic and form a plastic seal, whereby the heat and pressure areapplied by a crimping element yielding one or more regions of the sealwhere the average thickness of plastic in the crimped region is lessthan the initial combined thickness of the two plastic linings, andwhereby gas transport between said first phase and said second phasethrough said plastic seal is substantially less than a seal whereplastic is not crimped during sealing.
 59. A substantially gas-tightplastic-lined foil pouch with a perimeter seal, comprising two portionsof plastic-lined foil with plastic faces abutted and sealed together toform an enclosure containing a liquid phase and a gas phase, where saidperimeter seal is formed by applying sufficient heat and pressure tomelt the plastic and form a plastic perimeter layer, where the pressureis applied by a crimping element yielding one or more regions of theperimeter seal where the average thickness of plastic in the perimeterseal in the crimped regions is substantially less than the initialcombined thickness of the two plastic linings.
 60. A method of forming asubstantially gas tight seal in a plastic-lined foil pouch, comprising:(a) forming a pocket in a first plastic-lined foil, applying a portionof liquid into the pocket; (b) covering the pocket with a secondplastic-lined foil with the plastic faces abutted; and (c) sealing saidfirst and second plastic-lined foils together to form a perimeter seal,where said perimeter seal is formed by applying sufficient heat andpressure to melt the plastic and form a plastic perimeter layer, wherethe pressure is applied by a crimping element yielding one or moreregions of the perimeter seal where the average thickness of plastic inthe crimped regions is substantially less than the combined thickness ofthe two plastic linings, said seal forming a substantially gas tightpouch containing a liquid phase and a gas phase.
 61. The method of claim60, performed with the foil on a reel.
 62. The method of claim 60,wherein the pressure is applied with a jig that crimps the foil.
 63. Themethod of claim 60, wherein the heat and pressure is applied withultrasonic welding.
 64. A method of forming a substantially gas-tightplastic-lined foil pouch with a perimeter seal, comprising: (a) a firststep where two portions of plastic-lined foil with the plastic facesabutted are sealed together to form an enclosure with a perimeter sealcontaining a liquid phase and a gas phase, where said perimeter seal isformed by applying sufficient heat to melt the plastic and sufficientpressure to form a contiguous plastic perimeter seal, and (b) a secondstep where said perimeter seal is crimped to yield one or more regionsof the perimeter seal where the average thickness of plastic in thecrimped regions is substantially less than the combined thickness of thetwo plastic linings.
 65. A substantially gas-tight seal formed withplastic-lined foil, comprising: two portions of plastic-lined foil withthe plastic faces abutted where adjacent portions are sealed together toisolate a first phase from a second phase, where said seal is formed byapplying sufficient ultrasonic welding to melt the plastic and form aplastic seal, whereby the ultrasonic weld yields one or more regions ofthe plastic seal where the average thickness of plastic in the sealregion is substantially less than the initial combined thickness of thetwo plastic linings, and whereby gas transport between said first phaseand said second phase through said plastic seal is substantially lessthan a seal where the thickness of plastic is substantially that of thecombined thickness of two plastic linings.
 66. A substantially gas-tightplastic-lined foil pouch with a perimeter seal, comprising two portionsof plastic-lined foil with the plastic faces abutted and sealed togetherto form an enclosure containing a liquid phase and a gas phase, wheresaid perimeter seal is formed by applying an ultrasonic weld to melt theplastic and form a contiguous plastic perimeter layer, and force aportion of plastic from the seal region into at least a portion of theperimeter of the enclosure, whereby the average thickness of plastic inthe perimeter seal is less than the initial combined thickness of thetwo plastic linings.
 67. A method of forming a substantially gas tightseal in a plastic-lined foil pouch comprising: (a) forming a pocket in afirst plastic-lined foil; (b) applying a portion of liquid into thepocket; (c) covering the pocket with a second plastic-lined foil withthe plastic faces abutted; and (d) sealing said first and secondplastic-lined foils together to form a perimeter seal, where saidperimeter seal is formed by applying an ultrasonic weld to melt theplastic and force a portion of plastic from the seal region into thepocket, said seal forming a substantially gas tight pocket containing aliquid phase and a gas phase, whereby the average thickness of plasticin the perimeter seal is substantially less than the combined thicknessof the two plastic linings.
 68. A substantially gas-tight seal formedwith plastic-lined foil, comprising: two portions of plastic-lined foilwith the plastic faces abutted where adjacent portions are sealedtogether to isolate a first phase from a second phase, where said sealis formed by applying sufficient welding energy to substantially removeplastic from the seal region and melt the foil and form a metal-to-metalseal in said seal region.
 69. The seal of claim 68, wherein said weldingenergy is provided by ultrasonic energy or laser energy.
 70. Asubstantially gas-tight foil pouch with an inner plastic perimeter sealand an outer metal-to-metal seal, comprising: two portions of foil witha plastic lining on predetermined regions of the foil where the regionsand plastic faces are aligned, abutted and sealed together to form anenclosure, bounded by an inner plastic perimeter seal, containing aliquid phase and a gas phase, and where a surrounding portion of the twoportions of the foil are laser welded together forming an outermetal-to-metal seal.
 71. A substantially gas-tight pouch, comprising: aninner sealed plastic enclosure containing a liquid phase and a gasphase, and an outer sealed foil enclosure where two portions of foil arelaser welded together to form an outer metal-to-metal seal enclosingsaid plastic enclosure.